1. Field of the Invention
The present invention relates to asymmetric syntheses and intermediates for preparing enantiomer-enriched hydroxyphosphinyl derivatives.
2. Description of the Prior Art
Asymmetric Syntheses
Asymmetric synthesis is important in the pharmaceutical industry because often only one optically active isomer (enantiomer) has any beneficial therapeutic effect. Such is the case of the non-steroidal anti-inflammatory compound naproxen. The S-enantiomer of naproxen is an effective anti-arthritic drug, while the R-enantiomer is a known liver toxin. The differences in pharmacological effectiveness between two such enantiomers often makes it desirable to selectively synthesize one enantiomer over its mirror image.
It is known in the art that organic syntheses of pharmaceutical compounds often results in optically inactive racemic mixtures Racemic mixtures contain equal amounts of species having optically opposite activities and thereby cancel one another out. In order to obtain the desired enantiomeric compound from racemic mixtures it is necessary to separate the racemic mixture into its optically active components. Separation of enantiomers, known as optical resolution, can be carried out by physical sorting, direct recrystallisation, or other methods known in the art. Such separation methods are often slow, expensive and destructive to the compounds of interest. Because of these inherent problems in separation methods, more effort has been directed to employing asymmetric synthesis where one of the enantiomers is preferentially synthesized in larger amounts.
Accordingly, there is a need for asymmetric syntheses that provide good yields of optically active products and that have high stereoselectivity.
Hydroxyphosphinvl Derivatives
Hydroxyphosphinyl derivatives have recently been found to inhibit N-acetylated .alpha.-linked acidic dipeptidase (NAALADase). Such activity has proven to be useful in treating various diseases; conditions and disorders, including glutamate abnormalities (particularly stroke, Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS), spinal cord injury, alcoholism and nicotine dependence), and prostate diseases (particularly prostate cancer). Since the inhibition of NAALADase by hydroxyphosphinyl derivatives may be highly stereospecific and regiospecific, an enantiomerically pure hydroxyphosphinyl derivative would be desirable for optimal pharmacological activity. However, asymmetric reduction of ethylene substituted phosphoesters has been difficult to achieve. Accordingly, a need exists for new methods of reducing such compounds to synthesize enantiomerically-enriched hydroxyphosphinyl derivatives.